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Association of the 323/A3 Surface Glycoprotein with Tumor Characteristics and Behavior in Human Breast Cancer1

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Association of the 323/A3 Surface Glycoprotein with Tumor Characteristics and Behavior in Human Breast Cancer1 (CANCER RESEARCH 50. 3317-3321. June 1. 1990] Association of the 323/A3 Surface Glycoprotein with Tumor Characteristics and Behavior in Human Breast Cancer1 Atul K. Tandon, Gary M. Clark, Gary C. Chamness, and William L. McGuire2 Department of Medicine/Oncology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78284-7884 ABSTRACT antigen appears to be correlated with progression of the disease. The main focus of the present study was to determine more We have earlier described a monoclonal antibody (323/A3) against a fully the relationship between occurrence of 323/A3 protein M, 43,000 surface glycoprotein of MCF-7 human breast cancer cells with other variables as well as with clinical behavior in breast which shows considerable specificity for primary and metastatic breast tumors (Cancer Res., 46: 1306-1317, 1986). Here we report the occur cancer. rence of the 323/A3 antigen in a large cohort of primary breast tumors (n = 384) and its interrelationship with several clinically important MATERIALS AND METHODS variables. Frozen, stored tumor tissues were examined by a Western blot proce Materials and Reagents. Bicinchoninic acid (BCA) reagents (A and dure, and the level of 323/A3 protein in individual tumors was calculated B) for protein determination were purchased from the Pierce Chemical in arbitrary units based on the integrated M, 43,000 signal in tumors Co., Rockford, IL. Reagents for electrophoresis were obtained from compared with an MCF-7 internal standard. Thirty-six % (139 of 384) Bio-Rad Laboratories, Richmond, CA. Nitrocellulose membranes (0.45 of tumors were found to be positive for 323/A3. Higher frequencies of Mm) were purchased from Schleicher and Schuell, Keene, NH. '"I- 323/A3 protein were found in tumors larger than 2 cm (P = 0.03), tumors Labeled rabbit anti-mouse IgG was obtained from New England Nu with infiltrated lymph nodes (/' = 0.01), and tumors without estrogen clear, Boston, MA. All other chemicals used were of analytical purity receptor (P = 0.006). No significant relationship was found with patient grade or the best grade available. age, menopausa! status, or progesterone receptor status. Of the newer Acquisition and Storage of Human Breast Tumors. Tumor specimens clinical determinants proliferative rate (% S phase), DNA ploidy, and studied in this report were obtained from women undergoing surgery the lysosomal protease cathepsin D, but not the HER-2/neu oncogene for primary breast cancer in hospitals nationwide. Immediately after protein, were significantly correlated with 323/A3. The presence of 323/ surgical removal, a portion of each tumor specimen was snap frozen in A3 protein was also related to increased recurrence (P = 0.003) and liquid nitrogen and shipped to our laboratory on dry ice for steroid mortality (P = 0.036) after primary treatment. receptor analysis. All tissues were coded, mechanically pulverized in As an exposed surface antigen, this glycoprotein might be a useful the frozen state, and analyzed for receptors. The remaining powders target in radioimaging and immunotherapy of some human breast tumors, were stored in air-tight plastic tubes at -70°C.Tissues for the quanti- especially those having large size, infiltrated lymph nodes, deficient tation of 323/A3 antigen were obtained retrospectively from these estrogen receptor, high proliferative rate, abnormal DNA content, and biopsy specimens collected for clinical purposes unrelated to this inves high levels of cathepsin D, all of which are ominous indicators of tumor tigation. Sections 4 pm thick from formalin-fixed, paraffin-embedded behavior. tissues were stained with hematoxylin-eosin and examined under a microscope for the presence of tumor cells. All 384 specimens included in this study contained tumor cells, although the percentage of tumor INTRODUCTION cells varied considerably. Clinical Characteristics of Subjects and Follow-up. The clinical infor Although a number of tumor-associated cell surface antigens mation was abstracted from the individual patient chart. Tumors ana have been reported in breast cancer and have even been used in lyzed here were from a patient population ranging in age from 27 to therapeutic and imaging trials (1-12), the relationship of these 86 years with a median of 58 years. Lymph nodes were examined antigens with other known clinical determinants has not usually microscopically for the presence of tumor cells at the individual hos been examined. We have previously described a MAb,3 323/ pitals where surgery was performed. Lymph node involvement was A3, against a M, 43,000 surface glycoprotein of MCF-7 human considered negative when no lymph nodes contained tumor cells and positive if one or more nodes showed the presence of malignant cells. breast cancer cells (1). Based on a comparison by molecular Fifty-one % (195 of 384) of patients included in this investigation did weight and immunocytochemical tissue distribution, this M, not contain tumor extensions to the axillary lymph nodes. Of the node- 43,000 glycoprotein represents a protein previously undescribed positive patients, 62% (118 of 189) had more than 3 lymph nodes with either in breast cancer or in other tumors. Strong 323/A3 tumor infiltration. Tumor size (largest diameter) was recorded at the binding was observed to three human breast cancer cell lines time of surgery. Depending upon the size, tumors were divided into (MCF-7, T47D, and ZR-75), whereas two other human breast two groups for the purpose of statistical analysis. Of the 384 tumor cancer cell lines (MDA-231 and HBL-100) and three non-breast specimens studied in this report, 103 (27%) were less than or equal to cell lines displayed little or no binding (13). In histochemical 2 cm ¡ndiameter. Levels of ER and PgR in tumor cytosols are routinely studies, this antibody detected 75% of metastatic lymph nodes determined in our laboratory as described previously (14, 15). Tumors and 59% of primary breast tumors and showed some staining were designated positive if the receptor binding was >3 fmol for ER and >5 fmol for PgR per mg cytosol protein. in 20% of benign breast lesions (1), so that presence of the Proliferative rate (percentage of S phase) and ploidy (DNA content) Received 10/10/89; revised 2/23/90. were determined in our laboratory by flow cytometric analysis (16). The costs of publication of this article «eredefrayed in part by the payment Levels of the HER-2/ni>«oncogene protein and the M, 34,000 mature of page charges. This article must therefore be hereby marked advertisement in form of cathepsin D were quantitated by Western blotting and densi- accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1This work was supported by NIH Grant CA 30195. It was presented at the tometry of pertinent bands on the resulting autoradiograms as detailed 11th Annual San Antonio Breast Cancer Symposium. November 1988. before (17,18). Patients were followed for disease recurrence and overall 2Clinical Research Professor of the American Cancer Society. To whom survival as described previously (19). Median clinical follow-up time requests for reprints should be addressed, at University of Texas Health Science for patients still living was 65 months with a range of 16-168 months. Center. 7703 Floyd Curl Drive, San Antonio. TX 78284-7884. 3The abbreviations used are: MAb. monoclonal antibody; ER, estrogen recep Any postsurgical appearance of malignancy either near to or distant tor; PgR. progesterone receptor; 323/A3. a M, 43.000 surface glycoprotein first from the operated breast was considered as recurrence of disease. A identified in MCF-7 cells; SDS. sodium dodecyl sulfate. computer database containing continually updated clinical information 3317 Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 1990 American Association for Cancer Research. 323/A3 GLYCOPROTEIN IN BREAST CANCER on each patient was used for statistical analysis. MCF-7 Cells for 323/A3 Internal Standard. MCF-7 human breast cancer cells were cultured in Eagle's minimum essential medium sup plemented with 10 m.M4-(2-hydroxyethyl)-l-piperazineethanesulfonic acid, 1% nonessential amino acids (GIBCO), 2 HIM L-glutamine (GIBCO), 25 Mg/ml gentamicin (Irvine Scientific), 6 ng/ml bovine insulin, and 5% calf serum (K. C. Biologicals). Sodium bicarbonate A560 (0.2%) was added to adjust the final pH to approximately 7.2. Cells were allowed to grow at 37°Cin an atmosphere containing 5% CO2. Logarithmically growing MCF-7 cells close to confluency were har vested by a brief incubation with 1 mM EDTA in phosphate-buffered saline. Cells were washed twice with phosphate-buffered saline, and the cell pellets were stored at -70°Cuntil required for assay. Western 43KDQ Quantitation of 323/A3 Protein. Proteins were extracted from the Blot tumor tissues or cell pellets as described elsewhere (17). In brief, approximately 10 mg of powder from each tumor were exposed to 150 1234 567 8,.100 50 25, n\ of 5% SDS. Tubes were kept in a boiling water bath for 5 min. Clear Human Breast Tumors MCF-7Stds supernatant was collected after spinning the tubes at 13,000 x g for 2 (Units 323/A3) min. Residual insoluble material was once again extracted with 150 ^1 Fig. I. Solimi nani nal inn of 323/A3 protein in breasl tumors by Western blot of 5% SDS as described above, and the first and second supernatants and densitometry. The 323/A3 band at M, 43.000 (kDa) along with corresponding were combined. Protein concentration in the SDS extracts was deter densitometric scanning is shown. The 323/A3 content in specimens was calculated in arbitrary units based on an internal standard of human breast cancer MCF-7 mined by the BCA method (20). cells. The 323/A3 values for the 8 tumors shown here are 113, 3, 4, 0, 0.
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